SUMMARY The overall goal of the proposed training plan is to develop the fellowship applicant's fundamental knowledge, conceptual frameworks, research expertise, and professional skills to maximize his impact as a physician- scientist. This will be accomplished by an educational and research training plan through which the applicant will: 1) develop the knowledge base and technical expertise required to determine the epigenetic mechanisms of gene regulation in health and disease, 2) learn to integrate basic science discoveries with patient data to develop preclinical studies that lead to clinical trials and new standards of care, and 3) develop professional skills in communication, collaboration, and leadership. These goals will be achieved through a unique, inter-campus research training plan that integrates the resources of two universities to provide graduate and medical education (Loma Linda University) with an extramural research training experience (Pennsylvania State University). Research activities will focus on high-risk pediatric B-cell acute lymphoblastic leukemia (B-ALL) and upstream mediators of epigenetic regulation that can be targeted for treatment. Data from the research mentor/sponsor's laboratory implicate Casein Kinase II (CK2) as a major player in this disease and suggest that combination therapies targeting CK2 and its downstream pathways could be a game changer in the treatment of high-risk B-ALL. The overall goal of the research training plan is to define the role of CK2 in the oncogenesis of B-ALL and to evaluate the efficacy and epigenetic mechanisms of combination therapy targeting the CK2 pathway in high-risk B-ALL. CK2 functionally inactivates the Ikaros tumor suppressor. Pharmacological inhibition of CK2 can restore Ikaros' ability to regulate transcription in high- risk B-ALL. We have also demonstrated that treatment with the CK2 inhibitor, CX-4945, has therapeutic efficacy in patient-derived xenograft (PDX) models of high-risk B-ALL. These discoveries establish the feasibility of CK2 inhibitors as a targeted treatment for high-risk B-ALL. They also suggest that CK2 contributes to B-ALL oncogenesis by functionally inactivating the Ikaros tumor suppressor. Our recent preliminary data indicates that CK2 interferes with Ikaros' ability to repress transcription of genes associated with the folic acid metabolism pathway. High expression of these genes in leukemia is associated with resistance to the folic acid pathway inhibitor, methotrexate. Our overall hypothesis is that overexpression of CK2 plays a role in B-ALL oncogenesis through its effects on Ikaros-mediated tumor suppression. We also hypothesize that CK2 inhibitors can be used in combination with therapeutics that act on Ikaros targets (folic acid pathway genes) to effectively treat high-risk B-ALL. To test these hypotheses we propose the following aims: Specific Aim 1: Establish the therapeutic efficacy and epigenetic mechanisms of combination treatment with CK2 inhibitor and folic acid pathway inhibitor (methotrexate) in a preclinical model of high-risk B-cell acute lymphoblastic leukemia. Specific Aim 2: Determine the role of CK2 in leukemogenesis.